Despite an improved understanding of the metabolic vulnerabilities of some diseases, less progress has been made on understanding whether targeting specific pathways, like glucose metabolism, would be effective and tolerated as therapies. The long-term goal of this project is to understand the unique features of tissue-specific metabolism in order to validate viable targets for specific diseases. The overall objective of this proposal is to characterize the impact of a prototype metabolic therapy, the inhibition of glucose transport, on the metabolism of normal and hyperproliferative epidermal tissues. The central hypothesis is that genetically and chemically inhibiting glucose transport will prevent pathological hyperplasia, without affecting the normal function of the skin. This hypothesis is based on the novel finding that Glut1 deficient skin undergoes transcriptional and met- abolic reprogramming to allow for normal skin function and homeostasis, but is unable to proliferate in re- sponse to physiological stressors. A thorough understanding of the principles that underlie the differential met- abolic requirements of normal and proliferating tissues will validate glucose transport inhibition as a therapeutic target and facilitate the development of additional, novel therapies to target tissue-specific metabolism. This proposal will be achieved through three aims: 1) Determine how genetic inhibition of glucose transport rescues acute, imiquimod-induced psoriasiform hyperplasia. Glut1 deficient skin will be analyzed through histology, gene expression, and metabolomic assays. The impact of genetic inhibition of glucose transport and induced hyperplasia on metabolic flux will be assessed through established in vivo 13C isotopic labeling. 2) Determine whether the topical application of small-molecule inhibitors of glucose transport can a) improve markers of hy- perplasia in organotypic skin equivalents, and b) reverse chronic, UVB-induced hyperplasia in hairless mice. The topical application of small molecule inhibitors of glucose transport will first be optimized in organotypic cultures, and then those inhibitors will be tested for their ability to affect chronic hyperplasia in organotypic cul- ture models and in UVB-irradiated, hairless mice. 3) Assess whether pathways already implicated by the loss of Glut1 in mice are also affected in biopsies from patients who develop pathophysiological overexpression of Glut1. Completion of these proposed goals will facilitate the development of glucose transport inhibition as po- tential therapy for diverse hyperplastic skin diseases, including psoriasis, and also will significantly advance our understanding of how metabolism is regulated in normal and disease processes in vivo. Experts in genetics, molecular cell biology, metabolomics, pathology, and clinical patient registries will collaborate to assess the impact of targeting a specific metabolic pathway on multiple models of disease.